Polyenylphosphatidylcholine (PPC), a polyunsaturated phospholipid extract from soy beans, prevents the development of liver cirrhosis in animal models. Its mechanism of action is unknown. Based on the hypothesis that PPC might act by decreasing hepatic stellate cell proliferation, we studied the effect of PPC and its main components, dilinoleoylphosphatidylcholine (DLPC) and palmitoyl-linoleoylphosphatidylcholine (PLPC), on PDGF-induced stellate cell proliferation and intracellular signal transduction. Normal rat hepatic stellate cells in tissue culture were serumstarved, and incubated with 10ng/ml PDGF in the absence or presence of phospholipids. Cell proliferation was measured by 3H-thymidine incorporation. P44MAPK activation was determined by kinase assay, and AP-1 binding by electrophoretic mobility shift assay. PPC (200 ng/ml) significantly inhibited PDGF-induced proliferation (p < 0.05; ANOVA, n = 3) and antagonized PDGF-induced P44MAPK activation and AP-1 binding. This effect was mimicked by DLPC but not by PLPC. Neither DLPC nor PLPC prevented PDGF receptor activation. We conclude that PPC exerts a previously unrecognized effect on mitogen-induced stellate cell proliferation which may be mediated by DLPC. Inhibition of this cascade represents a potential mechanism for the inhibitory effect of PPC on hepatic fibrogenesis.